1. Filed of the Invention
This invention relates to compositions containing conjugates of N,N-dimethyldiatrizoic acid and methods for their use in diagnostic radiology. More particularly, the invention relates to compositions containing N,N-dimethyldiatrizoic acid or a conjugate thereof for use as hepatobiliary agents for x-ray CT imaging.
2. Reported Developments Roentgenographic examination utilizing X-rays and computed tomography (hereinafter CT) scans of fractures and other conditions associated with the skeletal system is routinely practiced without the use of contrast agents. X-ray visualization of organs containing soft tissues, such as the gastrointestinal tract, heart, lung, kidneys and spleen, requires the use of contrast agents which attenuate x-ray radiation. D. P. Swanson et al. in "Pharmaceuticals In Medical Imaging", 1990, MacMillan Publishing Company, provides an excellent background in medical imaging utilizing contrast agents and compositions therewith.
Roentgenographic examination of the GI tract are indicated for conditions of digestive disorders, changes in bowel habit, abdominal pain, GI bleeding and the like. Prior to radiological examination, administration of a radiopaque contrast medium is necessary to permit adequate delineation of the respective lumen or mucosal surface from surrounding soft tissues. Accordingly, a contrast medium is administered orally to visualize the mouth, pharynx, esophagus, stomach, duodenum and proximal small intestine. The contrast medium is administered rectally for examination of the distal small intestine and the colon.
The most widely used contrast agent for the visualization of the GI tract is barium sulfate administered as a suspension orally or rectally as an enema. (See, for example, U.S. Pat. Nos. 2,659,690; 2,680,089; 3,216,900; 3,235,462; 4,038,379; and 4,120,946.) Notwithstanding its relatively good contrast characteristics, negligible absorption from the GI tract following oral or rectal administration and speedy excretion form the body, barium sulfate has certain disadvantages. In the presence of intestinal fluids it lacks homogeneity and poorly adheres to mucus membranes which can result in poor x-ray images. In the colon, when administered as an enema, it flocculates and forms irregular clumps with fecal matter.
In addition to, or in place of barium sulfate, iodinated organic compounds have also been used as GI contrast agents since the iodine atom is an effective x-ray absorber. They have the most versatility and are utilized in the widest variety of procedures. They are very absorptive of x-rays with which the iodine interacts and produce a so-called photoelectric effect which is a large magnification in contrast caused by the photons stopped in the iodine-containing medium. The magnification of contrast exceeds the level that would be expected from relative changes in density. Because of this magnification, relatively low concentrations of the contrast agents can be utilized. (For iodinated agents see, for example, U.S. Pat. Nos.: 2,786,055; 3,795,698; 2,820,814; 3,360,436; 3,574,718; 3,733,397; 4,735,795; 5,047,228; 5,308,607; 5,310,538; 5,318,769; 5,334,370; 5,336,484 and 5,344,638.)
The desiderata for an ideal GI contrast agent includes: good toxicological profile; the ability to fill the entire bowel/lumen and evenly coat the gut mucosa so that the presence of the bowel is detectable when the lumen is not distended; nonirritation to the intestinal mucosa; and passage through the GI tract without producing artifacts or stimulating vigorous intestinal peristalsis.
We have found that the compounds of the present invention having these and other desirable characteristics in the GI tract do satisfy the requirements of an x-ray contrast agent when incorporated in suitable aqueous oral or rectal formulations for examination of the GI tract utilizing x-rays and CT scans.
During extensive investigation we have also discovered that the compounds of the present invention are eminently suitable for intravenous administration for CT imaging of organs, such as the kidneys and liver. It is well known by those skilled in the art that agents for intravenous administration must meet certain requirements that arc more stringent than the requirements for oral and rectal administration since the agents are directly introduced into the blood stream of the patient. The imagining of the organ or body section is accomplished by means of roentgenography commonly referred to as computed tomography (CT) or computerized axial tomography (CAT) in which the emergent x-ray beam is measured by a scintillation counter, the electronic impulses are recorded on a magnetic disk, and then processed by a computer for reconstruction display.